Activation of cytotoxic T cells by solid tumours?

Tumour-specific cytotoxic T cells (CTLs) are among the best-defined biological anticancer weapons. Nevertheless, they often fail to control tumour growth in vivo. Many reasons for this have been evoked tumours may actively inhibit CTLs, or may protect them selves from CTL recognition by various means. However, one does not necessarily need to postulate such active immune evasion mechanisms specifically acquired by tumour cells. In this review we argue that the failure of immune protection is due to the intrinsic inability of tumours to activate an effective immune response, and that many tumours are similar to normal issues in this respect. It is striking to see that the majority of the so-called immune escape mechanisms are not specifically acquired by selected tumour cells, but are common mechanisms shared between solid tumours and normal, healthy tissues. Immune responses are poor because tumour antigens do not efficiently localize to lymph follicles in lymphoid tissues, and are not efficiently presented to CTLs in an immunogenic context. The fact that tumours do not induce CTLs but are often susceptible to lymphocyte-mediated cytotoxicity indicates that more intensified immunization protocols should result in improved clinical outcome.     

Hydrophobic properties of model compounds with peptide-like chemical environment: N-acetyl-N′-methyl-amino acid amides

Summary Capacity factors in reversed-phase HPLC and distribution constants in octan-l-ol/water of N-acetyl-N-methylamino acid amides have been measured as a function of temperature. The HPLC capacity factors are proposed as estimates of the hydrophobicity of the amino acid side chains.We acknowledge the interest in this work of Dr H. van Rooy, Dr J. Kinkel, Prof. W. Soudijn and Prof. E. Tomlinson.     

Hydrolysis of N-phenylacetyl-α-methyl-α-amino acids by benzylpenicillinacylase

Summary Enzymatic hydrolysis of several racemic N-phenylacetyl--methyl--amino acids containing an additinal aliphatic, aromatic or polar substitutent on the chiral carbon atom, has been studied by using benzylpenicillincylase fromEscherichia coli A.T.C.C. 9637. Both the rate of hydrolysis and the stereoselectivity were found to be considerably lower than in the case of natural -amino acids. Steric and electronic factors in the side chains influencing the stereoselectivity are discussed.     

Scattering ofα-particles from nuclei

Zusammenfassung Nach einem Überblick über dieRutherfordsche Theorie der Ablenkung von -Teilchen im elektrostatischen Feld des Atomkernes wird auf kürzliche Streuexperimente hingewiesen. Die Streuung von -Teilchen an schweren Kernen ist einem optischen Beugungsphänomen ähnlich. Resonanzen wie sie in der Streuung an leichten Kernen beobachtet werden, sind akustischen Resonanzen vergleichbar.     

Extrahepatic 7α-hydroxylation of dehydroepiandrosterone

Zusammenfassung In verschiedenen Rattenorganen (Lunge, Niere, Milz, Blut, Muskelgewebe) konnte ein System nachgewiesen werden, das imstande ist,in vitro Dehydroepiandrosteron an der 7-Stellung zu hydroxylieren. Dies Ergebnis weist auf die allgemein mögliche extrahepatale und extraadrenale Steroidhydroxylation hin.     

Age distribution of circulatingα-interferon

Summary A sensitive radioimmunoassay showed that circulating -interferon in the plasma of healthy individuals was low in children and reached the highest level in the young adult, then declined gradually with age. Circulating -interferon was 0.201±0.059 ng/ml in males (n=19) and 0.184±0.076 ng/ml in females (n=14) at ages 30–39 years old. It was noted that circulating -interferon was maintained up to a certain level even in elderly individuals.     

Preferences of transmembrane helices for cooperative amplification of Gαs and Gαq signaling of the thyrotropin receptor

The majority of constitutively activating mutations (CAMs) of the thyroid-stimulating hormone receptor display a partially activated receptor. Thus, full receptor activation requires a multiplex activation process. To define impacts of different transmembrane helices (TMHs) on cooperative signal transduction, we combined single CAMs in particular TMHs to double mutations and measured second messenger accumulation of the G_αs and the G_αq pathway. We observed a synergistic increase for basal activity of the G_αs pathway, for all characterized double mutants except for two combinations. Each double mutation, containing CAMs in TMH2, 6 and 7 showed the highest constitutive activities, suggesting that these helices contribute most to G_αs-mediated signaling. No single CAM revealed constitutive activity for the G_αq pathway. The double mutations with CAMs from TMH1, 2, 3 and 6 also exhibited increase for basal G_αq signaling. Our results suggest that TMH2, 6, 7 show selective preferences towards G_αs signaling, and TMH1, 2, 3, 6 for G_αq signaling.     

Luteolytic potency of 16-phenoxy-derivatives of prostaglandin F2α

Summary The binding of 16-phenoxy derivatives of prostaglandin (PG) F₂ to rat luteal membranes, and also their abortifacient potency in pregnant rats, have been studied. Competitive binding studies with various PG-analogues were performed in ovaries of juvenile rats pretreated with PMSG and HCG, and in parallel studies the abortifacient potency of these substances was tested, in pregnant rats. It was observed that this class of derivatives bound to the PGF₂ receptor as well as, or even better than the parent compound PGF₂. Modifications in the carboxyl group at C-1 yielded derivatives with a higher affinity for the receptor, in decreasing order of effectiveness as follows:-COOR>COOH>OH. The data obtained from the binding studies also compared well with data on the abortifacient potency in pregnant rats. It is concluded that the addition of a phenoxy group to either the lower or upper side chain of PGF₂ may augment the binding to the receptor as well as the biological responses induced by the post receptor effect.     

Conversion of 17α-hydroxypregnenolone to cortisol

Zusammenfassung Nebennierenschnitte von Ratten, Meerschweinchen und Menschen synthetisierten 17-Hydroxyprogesteron, 11-Deoxycortisol und Cortisol aus 17-Hydroxypregnenolon. Diese Verbindung, als Ausgangsprodukt für die Cortisolsynthese, ist ebenso wirksam wie pregnenolon. Die Umwandlung von 17-Hydroxypregnenolon in Dehydroepiandrosteron verläuft weniger vollkommen als zu 17-Hydroxycorticoiden.     

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

In the present study we demonstrated that neurotoxin MPP⁺-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP⁺-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G₀/G₁ cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP⁺ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP⁺ and cell-cycle re-entry through retinoblastoma protein phosphorylation.     

α-andβ-activity of O-methylated derivatives of norepinephrine and epinephrine

Summary Metanephrine, iso-metanephrine, normetanephrine and isonormetanephrine were tested for - and -activity on various tissues obtained from rats, guinea-pigs and cats. It was found that methylation of the hydroxyl groups of norepinephrine or epinephrine in either the 3-or 4-position markedly reduces or abolishes -and -activity with the exception of the nictitating membrane of the cat. This receptor seems to show a tissue difference.Acknowledgment. W. H. V. would like to thank the Federal Republik of Germany for the U. S. Senior Scientist Award which enabled him to work at the Department of Pharmacology, University of Mainz, and to conduct part of this work. W. H. V. would also like to thank Prof. Dr E. Muscholl, Mainz, for his hospitality, help and advice during this stay.     

Über einheitliche Racemate des 1-Oxo-2-methyl-7-methoxy-octahydrophenanthren-2-carbonsäuremethylesters

Summary The racemic mixture of 1-oxo-2-methyl-7-methoxy-octahydrophenanthrene-2-carboxylic acid methyl esters has been separated into three crystalline racemates.     

Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

Inflammation occurs in many amyloidoses, but its underlying mechanisms remain enigmatic. Here we show that amyloid fibrils of human lysozyme, which are associated with severe systemic amyloidoses, induce the secretion of pro-inflammatory cytokines through activation of the NLRP3 (NLR, pyrin domain containing 3) inflammasome and the Toll-like receptor 2, two innate immune receptors that may be involved in immune responses associated to amyloidoses. More importantly, our data clearly suggest that the induction of inflammatory responses by amyloid fibrils is linked to their intrinsic structure, because the monomeric form and a non-fibrillar type of lysozyme aggregates are both unable to trigger cytokine secretion. These lysozyme species lack the so-called cross-β structure, a characteristic structural motif common to all amyloid fibrils irrespective of their origin. Since fibrils of other bacterial and endogenous proteins have been shown to trigger immunological responses, our observations suggest that the cross-β structural signature might be recognized as a generic danger signal by the immune system.     

The oxidative metabolism ofα-chlorohydrin and the chemical induction of spermatocoeles

Summary -Chlorohydrin (I) is oxidatively metabolized to -chlorolactic acid (III) and oxalic acid (IV). Deposition of calcium oxalate within the renal tubules is responsible for the toxic effects of-chlorohydrin and a similar action on the epididymis or epididymal blood vessels could initiate the formation of spermatocoeles from this and other male antifertility agents.     

Influence of the structure of theN-terminal extremity ofα-MSH on the melanophore stimulating activity of this hormone

Zusammenfassung Drei strukturelle Analoge des-MSH wurden synthetisiert und auf ihre Melanophoren-stimulierende Wirksamkeit untersucht. Für das Auftreten einer ausgeprägten biologischen Aktivität scheint die Anwesenheit einerN-Acetyl-Gruppe an dem Aminoende der Peptidkette wichtiger zu sein als das Vorhandensein der zwei ersten amino-endständigen Aminosäurereste der-MSH-Kette.     

Synthesis of a pregnancy-associatedα-macroglobulin by human leucocytes

Résumé Le sang des femmes enceintes peut contenir plusierus protéines sériques uniques en leur genre. Celle qui se présente le plus souvent est une -globuline de grand poids moléculaire. Un test in vitro utilisant l'incorporation de¹⁴C-glutamine ou³H-leucine dans la glycoprotéine a montré que celle-ci peut être synthétisée par des leucocytes.

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We thank Dr.J. E. O'Grady and Dr.A. Shephard for obtaining the blood samples. This work was supported by a grant from the Scottish Home and Health Department.     

Identification of 3α, 17α, 21-trihydroxy-5α-pregnane (allotetrahydro-17α-hydroxy-cortexone) and 3α,21-dihydroxy-5α-pregnane (allo-tetrahydro-cortexone) in human urine

Résumé Le 3, 17, 21-trihydroxy 5-pregnane (allo-tétrahydro-17-hydroxy-cortexone) et le 3,21-dihydroxy 5-prégane (allo-tétrahydro-cortexone) ont été identifiés dans l'urine humaine. Ces composés avaient les mêmes migrations chromatographiques avant ou après acétylation ou oxydation que les respectifs stéroïdes de synthèse.     

Purification of 20α-hydroxysteroid dehydrogenase from human erythrocytes

Summary 20-hydroxysteroid dehydrogenase was found in the supernatant after hemolysis of human erythrocytes, and the enzyme was isolated from the membrane-free hemolysate on a DEAE-cellulose column. The NADPH-generating system was essential for the reaction.Acknowledgments. We wish to thank Dr A. Tomoda, Department of Biochemistry, Kanazawa University School of Medicine, and Dr T. Yubisui, Department of Biochemistry, Medical College of Oita, for their advice and useful discussions.     

Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB₂) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB₂ and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB₂ and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB₂, but not GRα. Overall, our study demonstrates for the first time the existence of a CB₂-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB₂ as a new target for chronic inflammatory and neurodegenerative diseases.     

Effects of D-α-aminoadipate on physiologically evoked responses of cat dorsal horn neurones

Summary Microelectrophoretic administration of D--aminoadipate reversibly reduced excitatory responses of cat dorsal horn neurones evoked by iontophoretic glutamate and non-noxious peripheral stimuli but did not influence similar responses evoked by noxious peripheral stimuli or iontophoretic substance P.